Prevalence and Correlates of the Concurrence of Autism Spectrum Disorder and Obsessive Compulsive Disorder in Children and Adolescents: A Systematic Review and Meta-Analysis.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) are two common and impairing neurodevelopmental conditions with partial symptomatic overlap. The aim of this study is to systematically and meta-analytically examine the following: (i) the prevalence of an OCD diagnosis among young people with ASD, (ii) the prevalence of an ASD diagnosis among young people with OCD, and (iii) the clinical and therapeutic implications of such comorbidity. METHOD: A multistep literature search was performed from database inception until 17 November 2023. This PRISMA/MOOSE-compliant systematic review, registered in PROSPERO (CRD42023480543), identified studies reporting on the prevalence, sociodemographic, psychopathologic, prognostic, and therapeutic correlates of OCD and ASD concurrence in children and adolescents. A quantitative meta-analysis with random effects was conducted to analyse the pooled prevalence of OCD among samples with a mean age of < 18 years old with ASD and the prevalence of ASD among individuals under 18 with OCD. Sensitivity analyses were performed to investigate the effect of diagnostic criteria and different continents. Meta-regression analyses were conducted to examine the effect of gender, age, IQ, and OCD severity scores. A narrative review of the clinical and therapeutical implications of the comorbidity was provided. RESULTS: 42 studies were selected for the systematic review (SR), and 31 of them were also included in one of the meta-analyses. The pooled prevalence of OCD among ASD youth samples (n = 8916, mean age = 10.6 ± 1.6; 16.4% female) was 11.6% (95% confidence intervals [CI] = 6.9%; 18.8%), and the pooled prevalence of ASD among OCD children and adolescent samples (n = 6209, mean age = 14.1 ± 1.4; 45.7% female) was 9.5% (95% CI = 6.0%; 14.7%). Meta-regressions found a statistically higher prevalence of ASD among samples with a lower prevalence of females (ß = -4.7; 95%CI = -8.6; -0.8). Children with both OCD and ASD present higher rates of functional impairment, psychopathology, and other comorbidities, compared to youth with either of the disorders alone. CONCLUSIONS: OCD and ASD are highly concurrent conditions in youth, with symptomatic, prognostic, severity, and therapeutic implications. Future research should focus on conducting longitudinal cohort studies prospectively to determine development trajectories, along with randomized controlled trials to assess the efficacy of specific therapeutic interventions.

Health service and psychotropic medication use for mental health conditions among healthcare workers active during the Spain Covid-19 Pandemic - A prospective cohort study using web-based surveys.

Little is known about healthcare workers' (HCW) use of healthcare services for mental disorders. This study presents data from a 16-month prospective cohort study of Spanish HCW (n = 4,809), recruited shortly after the COVID-19 pandemic onset, and assessed at four timepoints using web-based surveys. Use of health services among HCW with mental health conditions (i.e., those having a positive screen for mental disorders and/or suicidal thoughts and behaviours [STB]) was initially low (i.e., 18.2 %) but increased to 29.6 % at 16-month follow-up. Service use was positively associated with pre-pandemic mental health treatment (OR=1.99), a positive screen for major depressive disorder (OR=1.50), panic attacks (OR=1.74), suicidal thoughts and behaviours (OR=1.22), and experiencing severe role impairment (OR=1.33), and negatively associated with being female (OR = 0.69) and a higher daily number of work hours (OR=0.95). Around 30 % of HCW with mental health conditions used anxiolytics (benzodiazepines), especially medical doctors. Four out of ten HCW (39.0 %) with mental health conditions indicated a need for (additional) help, with most important barriers for service use being too ashamed, long waiting lists, and professional treatment not being available. Our findings delineate a clear mental health treatment gap among Spanish HCW.

Gene expression imputation provides clinical and biological insights into treatment-resistant schizophrenia polygenic risk.

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS).  In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS.

Psychopharmacology in children and adolescents: unmet needs and opportunities.

Psychopharmacological treatment is an important component of the multimodal intervention approach to treating mental health conditions in children and adolescents. Currently, there are many unmet needs but also opportunities, alongside possible risks to consider, regarding the pharmacological treatment of mental health conditions in children and adolescents. In this Position Paper, we highlight and address these unmet needs and opportunities, including the perspectives of clinicians and researchers from the European College of Neuropsychopharmacology-Child and Adolescent Network, alongside those of experts by lived experience from national and international associations, via a survey involving 644 participants from 13 countries, and of regulators, through representation from the European Medicines Agency. We present and discuss the evidence base for medications currently used for mental disorders in children and adolescents, medications in the pipeline, opportunities in the development of novel medications, crucial priorities for the conduct of future clinical studies, challenges and opportunities in terms of the regulatory and legislative framework, and innovations in the way research is conducted, reported, and promoted.

Difficulties during delivery, brain ventricle enlargement and cognitive impairment in first episode psychosis.

BACKGROUND: Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances. METHODS: We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis-Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups. RESULTS: FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio. CONCLUSIONS: Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

Progressive loss of cortical gray matter in first episode psychosis patients with auditory hallucinations.

BACKGROUND: Previous longitudinal magnetic resonance imaging studies have shown progressive gray matter (GM) reduction during the earliest phases of schizophrenia. It is unknown whether these progressive processes are homogeneous in all groups of patients. One way to obtain more valid findings is to focus on the symptoms. Auditory hallucinations (AHs) are frequent and reliable symptoms of psychosis. The present study aims to analyze whether longitudinal changes in structural abnormalities in cortical regions are related to the presence of AHs and the intensity of psychotic symptoms in a large sample. METHODS: A Magnetic Resonance (MR) voxel-based morphometry analysis was applied to a group of 128 first episodes psychosis (FEP) patients (63 patients with AHs and 65 patients without AHs) and 78 matched healthy controls at baseline and at a 2-year follow-up. RESULTS: At baseline, FEP patients exhibited significant GM volume reductions in the temporal, frontal and precentral regions. At follow-up, FEP patients exhibited GM volume changes in the temporal, Rolandic, frontal, precentral and insula regions. At baseline, no significant differences were found between FEP patients with and without AHs. At follow-up, while FEP patients with AHs showed less GM volume in temporal and frontal lobes, non-AH FEP patients showed reductions in the frontal, precentral and fusiform areas. PANSS scores showed statistically significant correlations with GM volume reductions at baseline and follow-up. CONCLUSIONS: Brain cortical loss in the early phases of psychosis is not associated with potentially transitory AHs; however, brain structural changes may emerge as AHs appear in chronic patients.

Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies.

The efficacy and safety of bumetanide oral solution for the treatment of autism spectrum disorder (ASD) in children and adolescents was evaluated in two international, multi-center, randomized, double-blind, placebo-controlled phase III trials; one enrolled patients aged 7-17 years (SIGN 1 trial) and the other enrolled younger patients aged 2-6 years (SIGN 2). In both studies, patients were randomized to receive bumetanide oral solution twice daily (BID) or placebo BID during a 6-month double-blind treatment period. The primary endpoint was change in Childhood Autism Rating Scale 2 (CARS2) total raw score from baseline to Week 26. Key secondary endpoints included changes in Social Responsiveness Scale-2, Clinical Global Impression Scale, and Vineland Adaptive Behavior Scale. Each study enrolled 211 patients (bumetanide, n = 107; placebo, n = 104). Both studies were terminated early due to absence of any significant difference between bumetanide and placebo in the overall studied populations. In both studies, CARS2 total raw score decreased from baseline to Week 26 in the bumetanide and placebo groups, with no statistically significant difference between groups. No differences were observed between treatment groups for any of the secondary efficacy endpoints in either study. In both studies, treatment-emergent adverse events that occurred more frequently with bumetanide than placebo included thirst, polyuria, hypokalemia, and dry mouth. These large phase III trials failed to demonstrate a benefit of bumetanide for the treatment of pediatric ASD compared with placebo. Consequently, the sponsor has discontinued the development of bumetanide for the treatment of this condition. Trial registration: https://clinicaltrials.gov: SIGN 1: NCT03715166; SIGN 2: NCT03715153.

Autism care pathway in Europe.

BACKGROUND: Autism is a lifelong complex neurodevelopmental condition that affects brain development and behaviour with significant consequences for everyday life. Despite its personal, familial, and societal impact, Europe-wide harmonised guidelines are still lacking for early detection, diagnosis, and intervention, leading to an overall unsatisfactory autistic person and carer journey. METHODS: The care pathway for autistic children and adolescents was analysed in Italy, Spain and the UK from the perspective of carers (using a survey aimed at caregivers of autistic children 0-18 years old), the autistic community, and professionals in order to identify major barriers (treatment gaps) preventing carers from receiving information, support, and timely screening/diagnosis and intervention. RESULTS: Across all three countries, analysis of the current care pathway showed: long waits from the time carers raised their first concerns about a child's development and/or behaviour until screening and confirmed diagnosis; delayed or no access to intervention once a diagnosis was confirmed; limited information about autism and how to access early detection services; and deficient support for families throughout the journey. CONCLUSIONS: These findings call for policy harmonisation in Europe to shorten long wait times for diagnosis and intervention and therefore, improve autistic people and their families' journey experience and quality of life.

Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy.

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes.

Identifying risk factors for predominant negative symptoms from early stages in schizophrenia: A longitudinal and sex-specific study in first-episode schizophrenia patients.

BACKGROUND: People with schizophrenia and predominant negative symptoms (PNS) present a different clinical and functional profile from those without such symptomatology. Few studies have examined the risk factors and the incidence of PNS in first-episode schizophrenia patients (FES) and differentiating by sex. This study aims to assess prevalence, demographic and clinical characteristics related to PNS from early stages and to study if there are sex-specific features in terms of developing PNS. METHODS: In a sample of 121 FES patients derived from a multicentre and naturalistic study, those who developed PNS at 12-months were identified. Environmental, clinical, functional, and cognitive ratings were examined longitudinally. Binary logistic regressions were applied to detect baseline risk factors for developing PNS at one-year follow-up. RESULTS: In the present FES cohort, 24.8% of the patients (n=30) developed PNS (20% of the women, 27.6% of the men). Compared to non-PNS (75.2%, n=91), at baseline, PNS group had more negative (t=-6.347; p<0.001) and depressive symptoms (t=-5.026; p<0.001), poorer premorbid adjustment (t=-2.791; p=0.006) and functional outcome (t=-2.649; p<0.001), more amotivation (t=-7.333; p<0.001), more expressivity alterations (t=-4.417; p<0.001), worse cognitive reserve (t=2.581; p<0.011), a lower estimated intelligent quotient (t=2.417; p=0.017), worse verbal memory (t=2.608; p=0.011), and worse fluency (t=2.614; p=0.010). Regressions showed that the premorbid adjustment was the main predictor of PNS in females (p=0.007; Exp(B)=1.106) while in males were a worse verbal memory performance (p=0.031; Exp(B)=0.989) and more alterations in the motivation domain (p=0.001; Exp(B)=1.607). CONCLUSIONS: A different baseline clinical profile and notable risk factors differences in the development of PNS between males and females were found. Results suggest that sex may be an important confounder in studies comparing schizophrenia patients with predominant and non-predominant negative symptomatology.

Association of Prolactin, Oxytocin, and Homocysteine With the Clinical and Cognitive Features of a First Episode of Psychosis Over a 1-Year Follow-Up.

BACKGROUND: The clinical debut of schizophrenia is frequently a first episode of psychosis (FEP). As such, there is considerable interest in identifying associations between biological markers and clinical or cognitive characteristics that help predict the progression and outcome of FEP patients. Previous studies showed that high prolactin, low oxytocin, and high homocysteine are factors associated with FEP 6 months after diagnosis, at which point plasma levels were correlated with some clinical and cognitive characteristics. METHODS: We reexamined 75 patients at 12 months after diagnosis to measure the evolution of these molecules and assess their association with clinical features. RESULTS: At follow-up, FEP patients had lower prolactin levels than at baseline, and patients treated with risperidone or paliperidone had higher prolactin levels than patients who received other antipsychotic agents. By contrast, no changes in oxytocin and homocysteine plasma levels were observed between the baseline and follow-up. In terms of clinical features, we found that plasma prolactin and homocysteine levels were correlated with the severity of the psychotic symptoms in male FEP patients, suggesting that they might be factors associated with psychotic symptomatology but only in men. Together with oxytocin, these molecules may also be related to sustained attention, verbal ability, and working memory cognitive domains in FEP patients. CONCLUSION: This study suggests that focusing on prolactin, oxytocin, and homocysteine at a FEP may help select adequate pharmacological treatments and develop new tools to improve the outcome of these patients, where sex should also be borne in mind.

The polygenic basis of relapse after a first episode of schizophrenia.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

Traumatic stress symptoms among Spanish healthcare workers during the COVID-19 pandemic: a prospective study.

AIM: To investigate the occurrence of traumatic stress symptoms (TSS) among healthcare workers active during the COVID-19 pandemic and to obtain insight as to which pandemic-related stressful experiences are associated with onset and persistence of traumatic stress. METHODS: This is a multicenter prospective cohort study. Spanish healthcare workers (N = 4,809) participated at an initial assessment (i.e., just after the first wave of the Spain COVID-19 pandemic) and at a 4-month follow-up assessment using web-based surveys. Logistic regression investigated associations of 19 pandemic-related stressful experiences across four domains (infection-related, work-related, health-related and financial) with TSS prevalence, incidence and persistence, including simulations of population attributable risk proportions (PARP). RESULTS: Thirty-day TSS prevalence at T1 was 22.1%. Four-month incidence and persistence were 11.6% and 54.2%, respectively. Auxiliary nurses had highest rates of TSS prevalence (35.1%) and incidence (16.1%). All 19 pandemic-related stressful experiences under study were associated with TSS prevalence or incidence, especially experiences from the domains of health-related (PARP range 88.4-95.6%) and work-related stressful experiences (PARP range 76.8-86.5%). Nine stressful experiences were also associated with TSS persistence, of which having patient(s) in care who died from COVID-19 had the strongest association. This association remained significant after adjusting for co-occurring depression and anxiety. CONCLUSIONS: TSSs among Spanish healthcare workers active during the COVID-19 pandemic are common and associated with various pandemic-related stressful experiences. Future research should investigate if these stressful experiences represent truly traumatic experiences and carry risk for the development of post-traumatic stress disorder.

Autism with co-occurring epilepsy care pathway in Europe.

BACKGROUND: Autism and epilepsy often occur together. Epilepsy and other associated conditions have a substantial impact on the well-being of autistic people and their families, reduce quality of life, and increase premature mortality. Despite this, there is a lack of studies investigating the care pathway of autistic children with co-occurring epilepsy in Europe. METHODS: We analyzed the care pathway for autistic children with associated epilepsy in Italy, Spain, and the United Kingdom from the perspective of caregivers (using a survey aimed at caregivers of autistic children 0-18 years old), the autistic community, and professionals, in order to identify major barriers preventing caregivers and autistic children from receiving timely screening and treatment of possible co-occurring epilepsy. RESULTS: Across all three countries, an analysis of the current care pathway showed a lack of systematic screening of epilepsy in all autistic children, lack of treatment of co-occurring epilepsy, and inappropriate use of antiepileptic drugs. A major challenge is the lack of evidence-based harmonized guidelines for autism with co-occurring epilepsy in these countries. CONCLUSIONS: Our findings show both heterogeneity and major gaps in the care pathway for autism with associated epilepsy and the great efforts that caregivers must make for timely screening, diagnosis, and adequate management of epilepsy in autistic children. We call for policy harmonization in Europe in order to improve the experiences and quality of life of autistic people and their families.

Differences in Patterns of Stimulant Use and Their Impact on First-Episode Psychosis Incidence: An Analysis of the EUGEI Study.

BACKGROUND: Use of illegal stimulants is associated with an increased risk of psychotic disorder. However, the impact of stimulant use on odds of first-episode psychosis (FEP) remains unclear. Here, we aimed to describe the patterns of stimulant use and examine their impact on odds of FEP. METHODS: We included patients with FEP aged 18-64 years who attended psychiatric services at 17 sites across 5 European countries and Brazil, and recruited controls representative of each local population (FEP = 1130; controls = 1497). Patterns of stimulant use were described. We computed fully adjusted logistic regression models (controlling for age, sex, ethnicity, cannabis use, and education level) to estimate their association with odds of FEP. Assuming causality, we calculated the population-attributable fractions for stimulant use associated with the odds for FEP. FINDINGS: Prevalence of lifetime and recent stimulant use in the FEP sample were 14.50% and 7.88% and in controls 10.80% and 3.8%, respectively. Recent and lifetime stimulant use was associated with increased odds of FEP compared with abstainers [fully adjusted odds ratio 1.74,95% confidence interval (CI) 1.20-2.54, P = .004 and 1.62, 95% CI 1.25-2.09, P < .001, respectively]. According to PAFs, a substantial number of FEP cases (3.35% [95% CI 1.31-4.78] for recent use and 7.61% [95% CI 3.68-10.54] for lifetime use) could have been prevented if stimulants were no longer available and the odds of FEP and PAFs for lifetime and recent stimulant use varied across countries. INTERPRETATION: Illegal stimulant use has a significant and clinically relevant influence on FEP incidence, with varying impacts across countries.

Examining the association between exposome score for schizophrenia and cognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

BACKGROUND: People with schizophrenia spectrum disorders (SSD) frequently present cognitive impairments. Here, we investigated whether the exposome score for schizophrenia (ES-SCZ) - a cumulative environmental exposure score - was associated with impairments of neurocognition, social cognition, and perception in patients with SSD, their unaffected siblings, and healthy controls. METHODS: This cross-sectional sample consisted of 1200 patients, 1371 siblings, and 1564 healthy controls. Neurocognition, social cognition, and perception were assesed using a short version of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Degraded Facial Affect Recognition Task (DFAR), and the Benton Facial Recognition Test (BFR), respectively. Regression models were used to analyze the association between ES-SCZ and cognitive domains in each group. RESULTS: There were no statistically significant associations between ES-SCZ and cognitive domains in SSD. ES-SCZ was negatively associated with T-score of cognition in siblings (B=-0.40, 95% CI -0.76 to -0.03) and healthy controls (B=-0.63, 95% CI -1.06 to -0.21). Additionally, ES-SCZ was positively associated with DFAR-total in siblings (B=0.83, 95% CI 0.26 to 1.40). Sensitivity analyses excluding cannabis use history from ES-SCZ largely confirmed the main findings. CONCLUSIONS: Longitudinal cohorts may elucidate how environmental exposures influence the onset and course of cognitive impairments in trans-syndromic psychosis spectrum.

Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation.

Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders and epilepsy. Despite their polygenic nature, genome-wide association studies have not reported a significant contribution of common genetic variation to comorbidity between both conditions. Analysis of common genetic variation affecting specific shared pathways such as miRNA dysregulation could help to elucidate the polygenic mechanisms underlying comorbidity between autism spectrum disorders and epilepsy. We evaluated here the role of common predisposing variation to autism spectrum disorders and epilepsy across target genes of 14 miRNAs selected through bibliographic research as being dysregulated in both disorders. We considered 4,581 target genes from various in silico sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected (p = 0.0228). Moreover, polygenic transmission disequilibrium test on an independent cohort of autism spectrum disorders trios (N = 233) revealed an under-transmission of autism spectrum disorders predisposing alleles within miRNAs' target genes across autism spectrum disorders trios without comorbid epilepsy, thus reinforcing the negative relationship at the common genetic variation between both traits. Our study provides evidence of a negative relationship between autism spectrum disorders and epilepsy at the common genetic variation level that becomes more evident when focusing on the miRNA regulatory networks, which contrasts with observed clinical comorbidity and results from rare variation studies. Our findings may help to conceptualize the genetic heterogeneity and the comorbidity with epilepsy in autism spectrum disorders.

Role of cortical excitatory/inhibitory imbalance in autism spectrum disorders from a symptom severity trajectories framework: a study protocol.

BACKGROUND: There is considerable evidence reporting an excitatory/inhibitory (E/I) cortical imbalance in autism spectrum disorders (ASD). However, previous findings on the direction of this imbalance and its relationship to ASD symptomatology are heterogeneous. Some factors contributing to these mixed results might be the methodological differences between studies assessing the E/I ratio and the intrinsic variability within the autistic spectrum. Studying the evolution of ASD symptoms and the factors that modulate it might help to explain and reduce this variability. Here we present a study protocol to explore the longitudinal role of E/I imbalance in ASD symptoms, combining different approaches to measure the E/I ratio and using the trajectories of symptom severity as a framework. METHODS: This observational two time-point prospective study assesses the E/I ratio and the evolution of the behavioural symptoms in a sample of at least 98 participants with ASD. Participants are enrolled at 12 to 72 months of age and followed from 18 to 48 months after. A comprehensive battery of tests is applied to evaluate ASD clinical symptoms. The E/I ratio is approached from electrophysiology, magnetic resonance, and genetics. We will calculate the individual change for the main ASD symptoms and, based on that, we will define the trajectories of symptom severity. Then, we will investigate the correlation between measures of excitation/inhibition balance and autistic symptomatology cross-sectionally, as well as the ability of these measurements to predict changes in symptoms over time. DISCUSSION: This study presents a robust multisystemic approach to the E/I imbalance theory in autism and its relation to divergent symptom trajectories. That setting will allow us to relate and compare the neurobiological information coming from different sources and its impact on behavioural symptoms while accounting for the high variability in ASD. The findings derived from this study could contribute to the ASD biomarkers research and might provide valuable evidence for the development of more personalized treatments in ASD.

The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.

In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review.

OBJECTIVE: The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials. METHODS: A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included. RESULTS: A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis." CONCLUSIONS: There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.